Review Article Hepatocellular Carcinoma in...

Review ArticleHepatocellular Carcinoma in Pakistan: National Trendsand Global Perspective

Abu Bakar Hafeez Bhatti,1 Faisal Saud Dar,1 Anum Waheed,2 Kashif Shafique,3

Faisal Sultan,4 and Najmul Hassan Shah5

1Department of HPB and Liver Transplantation, Shifa International Hospital, Islamabad, Pakistan2Sind Medical College, Karachi, Pakistan3Department of Public Health, Dow University of Health Sciences, Karachi, Pakistan4Department of Infectious Diseases, Shaukat KhanumMemorial Cancer Hospital and Research Center, Lahore, Pakistan5Department of Transplant Hepatology and Gastroenterology, Shifa International Hospital, Islamabad, Pakistan

Correspondence should be addressed to Abu Bakar Hafeez Bhatti; [email protected]

Received 4 November 2015; Revised 4 January 2016; Accepted 5 January 2016

Academic Editor: Nicola Silvestris

Copyright © 2016 Abu Bakar Hafeez Bhatti et al.This is an open access article distributed under theCreativeCommonsAttributionLicense, which permits unrestricted use, distribution, and reproduction in anymedium, provided the originalwork is properly cited.

Hepatocellular carcinoma (HCC) ranks second amongst all causes of cancer deaths globally. It is on a rise in Pakistan and mightrepresent the most common cancer in adult males. Pakistan contributes significantly to global burden of hepatitis C, which isa known risk factor for HCC, and has one of the highest prevalence rates (>3%) in the world. In the absence of a national cancerregistry and screening programs, prevalence of hepatitis andHCConly represents estimates of the realmagnitude of this problem. Inthis review, we present various aspects of HCC in Pakistan, comparing and contrasting it with the global trends in cancer care.Thereis a general lack of awareness regarding risk factors of HCC in Pakistani population and prevalence of hepatitis C has increased.In addition, less common risk factors are also on a rise. Majority of patients present with advanced HCC and are not eligible fordefinitive treatment. We have attempted to highlight issues that have a significant bearing on HCC outcome in Pakistan. A set ofstrategies have been put forth that can potentially help reduce incidence and improve HCC outcome on national level.

1. Introduction

Cancer is a leading cause of death worldwide and accountedfor 8.2 million deaths in the year 2012. Hepatocellular carci-noma (HCC) is the second most common cause of cancerdeath in the world with 745,000 deaths in the year 2012.In 2013, the World Health Organization (WHO) launched“Global Action Plan for the Prevention and Control of Non-communicable Diseases 2013–2020.” The primary objectiveof this plan is to reduce premature mortality due to cancer,cardiovascular and respiratory disease, and diabetes by 25%[1].

Pakistan stands at the crossroads of socioeconomic inse-curity and a keen desire for change [2]. It is the sixth mostpopulous country in the world with estimated population of182,142,594. As a low income country, we lag behind in var-ious important determinants of healthcare when compared

with peer countries. Based on WHO statistics, only 2.7% oftotal GDP is allocated to health sector (2012), infantmortalityis 75.5 per 1000 live births (2012), maternal mortality is 170per 100,000 live births (2013), and total health expenditureis 77$ per capita (2012). It is also estimated that 78% of ourpopulation pays out of pocket, private sector provides 3/4 oftotal healthcare, and there are twice asmany doctors as nursesfor our patients [3].

Cancer incidence and mortality are increasing in thedevelopingworld. Pakistan faces sinister limitations in cancercare that have an adverse impact on patient outcomes [4].A steady increase in the incidence of hepatobiliary cancershas been observed. Based on results of a reliable hospital-based registry in Pakistan, hepatobiliary cancers are the mostcommonmalignancy in adultmales and represent 10.7%of allcancers [5]. The age standardized rate for HCC in Pakistan is7.6 per 100,000 persons per year for males and 2.8 for females

Hindawi Publishing CorporationGastroenterology Research and PracticeVolume 2016, Article ID 5942306, 10 pageshttp://dx.doi.org/10.1155/2016/5942306

2 Gastroenterology Research and Practice

[6–8]. Our knowledge on HCC in Pakistani population islimited and primarily reflects single center experiences. Dataon HCC is derived from hepatitis B (hep-B) and hepatitis C(hep-C) patients and we are unaware of the natural history ofnon-hep-B/hep-C HCC in our population [9]. It is estimatedthat 60–70% HCC in Pakistan is attributable to hep-C. Thisis different from many other Asian Pacific countries wherehep-B remains the predominant etiology [10–13]. Cancer carein developing countries is compromised but HCC is uniquein a number of ways. It has geographical variation, treatmentremains controversial, and resource intensive and technicalcompetency alters the outcome considerably. Additionally,various obstacles limit access to standard healthcare anda delayed diagnosis unfortunately yields poor outcomes.Therefore applicability of established guidelines remainsquestionable in Pakistan and yet we lack a national consensuson HCC management.

Here, we have reviewed the epidemiology of HCC alongwith diagnostic interventions and treatments offered to Pak-istani patients. Factors that lead to late presentation havealso been discussed. We have elaborated upon the impact ofemerging therapies on HCC in Pakistan and attempted tooutline guidelines for better provision of care to our patients.

2. Risk Factors and Epidemiology

Well known risk factors for HCC include alcohol consump-tion, chronic infection with hepatitis C and hepatitis B,autoimmune hepatitis, hereditary hemochromatosis, alpha-1 antitrypsin deficiency, Wilson disease, and porphyrias [16,17].There is increasing evidence that diabetes and obesity arelinked to HCC [18–20].

2.1. Pakistan’s Outlook. In the absence of a national registryfor cancer patients, data primarily comes from single centerexperiences or scattered regional registries [6–8, 21, 22]. Mostpatients present in the fifth decade of life [23–25]. Hep-C isthe most common etiology in up to 58% patients and hep-B in 25.3% cases [13]. Results from larger studies (𝑁 ≥ 100)on HCC are conflicting where anti-HCV antibody positivityranges between 24 and 72.5% while HbsAg positivity variesbetween 13.1 and 51.2% [9, 26–31]. This can be attributedto patchy nature of available information, high prevalenceof hep-C in certain regions of the country, and lack ofnational cancer surveillance. Analysis of molecular evolutionpoints towards a distinct phylogenetic cluster of HCV-IIIain our region around 1920s which was followed by a rapidexponential growth in 1950s. As a result, epidemic spreadof HCV-IIIa occurred in Pakistan much earlier than othercountries [11]. Factors implicated in spread of hep-C virusinclude a predominantly rural population (66%), illiteracy,unscreened blood products, and misuse of injectables [32].Use of unsterilized instruments for shaving, minor surgicalprocedures, and circumcision is common in certain partsof Pakistan. It was shown that up to 48% barbers useunsterile blades for shaving [33]. This is probably why hep-B is the major factor responsible for HCC in developingAsian countries but not the most common etiology inPakistan [34]. A rise in non-hep-B-hep-C HCC has also

been observed. Underlying factors include rising incidenceof diabetes, obesity, and aflatoxins [13, 35–37].

To summarize, risk factors for HCC are not different inPakistan than the rest of the world. Relative frequency ofrisk factors however is variable and hep-C is by far the mostcommon etiology. As demonstrated in Figure 1, Pakistanis amongst the few countries in the world with the >3%prevalence of anti-HCV antibody. We remain unaware ofthe exact prevalence of non-hep-B-C HCC in Pakistan butincreasingly sedentary life style, obesity, diabetes, and poorquality of food have an important role to play.

3. Incidence and Mortality

Approximately 85% of global liver cancer burden is in Asiaand Africa. China, Korea, and Japan are Asian countries withincidence greater than 20/100,000 population. In contrast,Northern Europe andNorthAmerica are low incidence zoneswith incidence of HCC < 10/100,000 population.

3.1. Pakistan’s Outlook. HCC is associated with male gender.It was shown that Pakistan is amongst few countries alongwith Zimbabwe, Columbia, and Costa Rica with no genderpredilection but this might be changing now [34, 35]. Inci-dence of HCC in Pakistan is on a rise and correlates well withincreasing exposure to risk factors forHCC in our population[10]. Recent results show that hepatobiliary cancers mightrepresent themost commonmalignancy in adultmales in ourpopulation [5]. Based on available data, age standardized ratefor HCC in Pakistan is 7.6 per 100,000 persons per year formales and 2.8 for females [6–8].These estimates are based onhospital-based data and do not reflect the true population-based prevalence of HCC in recent years.

4. Screening

HCC has a median subclinical period of 3.2 years. In thisperiod screening has the highest impact with early detectionand potential for cure [38, 39]. Ultrasound (US) can detecttumors as small as 1.6 ± 0.6 cm [40]. Although US hassensitivity and specificity of >90% in detecting HCC, itsefficiency is compromised in liver cirrhosis. Its yield largelydepends on expertise of ultrasonographer [41].

Significant differences in regional guidelines on HCCscreening and diagnosis exist. European association on studyof liver-European organization for research and treatmentof cancer (EASL-EORTC) recommends against the use ofserum alpha fetoprotein (AFP) for regular screening given itslow specificity and additional cost per primary liver cancerdetected ($1982 (US alone) versus $3639 (AFP + US)) [15,42–44]. Asian Oncology Summit (AOS) recommends 3–6 monthly US with serum AFP. AOS guidelines are theleast stringent given the high incidence of risk factors (hep-B and hep-C) and HCC in this region. In addition AOSrecommends an AFP > 400 ng/mL to be diagnostic for HCCin high risk patients [45, 46].

4.1. Pakistan’s Outlook. Majority of patients with risk factorsforHCCdonot undergo screening.Wedonot have nationally

Gastroenterology Research and Practice 3

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accepted guidelines for screening high risk patients andphysicians at large have a variable practice in terms of choiceof investigations and time period between them. The mostcommon trend is 6 monthly US and serum AFP level [47].Many a time, screening US is performed by inexperiencedsonographers. Background cirrhosis makes interpretation ofUS findings difficult. Less than 10% patients are diagnosedwith HCC on screening in Pakistan [9, 13] and that perhapsexplains the delayed presentation and poor prognosis inmajority of HCC patients. The association between elevatedAFP and HCC diagnosis is variable. HCC might be presentin 7.5% to 100% patients with raised AFP [13, 27, 48–50].Thisheterogeneity primarily stems from variable cut-offs used todefine elevated AFP levels.

In summary, as low as 10% patients in Pakistan withrisk factors for HCC undergo regular screening and majorityof patients are diagnosed when they are symptomatic. Forthose who are screened; US and AFP are the most frequentlyperformed investigations but the time duration between these

investigations, cut-off for elevated AFP, and sonographers’technical competency remain grey areas. Recently, Pakistansociety for study of liver disease (PSSLD) has recommended6 monthly US for screening in cirrhotic patients.

5. Diagnosis and Staging

Diagnostic criteria in HCC remain controversial. This isparticularly true for lesions < 1 cm in size. For lesions >1 cm in size, typical features on CT or MRI are sufficientfor establishing a diagnosis. National comprehensive can-cer network (NCCN) and EASL-EORTC recommend 4–6monthly surveillance with US, CT, or MRI for lesions < 1 cmin size if they do not exhibit typical arterial enhancement andvenouswashout onCTorMRI. For lesions> 1 cm but atypicalfeatures on imaging, biopsy is recommended if it is likely toalter management [15, 41]. AOS however recommends con-sidering < 1 cm lesions with typical characteristics as HCC.AOS guidelines seem more applicable to Asian continent


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where HCC is more common, hepatitis B and hepatitis Care prevalent, and appropriate surveillance is difficult. Inaddition AFP > 400 is also diagnostic for HCC. Biopsy isrecommended in patients with a doubtful diagnosis [45, 46].

According to recently concluded BRIDGE study, themost common stage at presentation for patients with HCCremains BCLC stage C except in Japan and Taiwan [14]. Boththese countries have initiated national surveillance programswhich are still lacking in North America, Europe, and China[51–54].

5.1. Pakistan’s Outlook. Only 1.7% patients are diagnosed onCT findings alone while various combinations of CT, AFP,and histopathology are used in 62.5% patients [28]. Latepresentation and advanced cirrhosis in majority patients arecontributory. Since fewer than 10% patients are picked upon screening in Pakistan, patients usually have large tumors(≥8 cm) at the time of diagnosis. Tumors larger than 5 cm areseen in 44.3% patients and at presentation; 52–62% patientshave more than 1 tumor nodule. In addition 46–87% patientshave Child-Pugh stage B or C. Around 86%patients belong toOkuda class II or III and less than 15% patients are amenableto any form of definitive treatment [9, 28].

To summarize, patients with HCC generally haveadvanced disease at presentation and very few of them areeligible for definitive treatment. Since no local guidelinesexist for diagnosis ofHCC,majority of patients end up under-going an array of expensive investigations for establishing adiagnosis.

6. Treatment and Survival

HCChas a poor prognosis even in developed countries and 5-year survival is only 10%. Survival is evenworse in developingcountries and mortality is roughly equivalent to incidencerates [16]. According to 2015 statistics of International Agencyfor Research on Cancer (IARC), the mortality to incidenceratio for HCC is 0.95 and geographical patterns of incidenceto mortality are nearly uniform [55]. Early detection of HCCis critical in ensuring optimal treatment. Tumor characteris-tics (size, multinodularity, and vascular invasion), underlyingliver function (Child-Pugh score) and performance status

(Eastern Cooperative Oncology Group performance status),play an important role in survival [56–58].

Since prognosis of HCC depends on multiple factors,various algorithms and guidelines have been adopted buthave failed to satisfactorily address issues in HCC man-agement. The most widely used algorithm is BarcelonaClinic Liver Cancer (BCLC) staging system. It incorporatestumor characteristics, liver function, and performance statusof an individual patient for allocation to different stages.Patients in stages 0 and A are eligible for potentially curativetreatment options like surgical resection, transplantation,and local ablation. For patients in stage B, transarterialchemoembolization (TACE) is utilized. Stage C patients aretreated with Sorafenib while stage D (terminal) patientsare managed supportively [59–61]. Global trends in HCCtreatment are not uniform and are dictated by data collectioninstruments, availability of treatment facilities, and technicalskills. Treatment may vary for the same stage across differentregions. TACE is the most frequently used first treatment inNorthAmerica, Europe, China, and SouthKorea; PEI/RFA inJapan; and resection in Taiwan (Figure 2) [14].

Since 25–70% patients with HCC have advanced stageat presentation [62–66], chemotherapy provides minimalbenefit and survival with Sorafenib does not extend beyonda median of 2-3 months [67, 68]. Based on results ofclinical trials, median overall survival (OS) is 20 monthsfor stage B HCC, 10 months for Stage C HCC treated withSorafenib, and 3 months for stage D [67, 69]. It must benoted that these guidelines are not applicable to all patientsand treatment decisions for individual patients should ideallybe personalized. Given the complexity of disease, decisionsfor individual patients should be taken by multidisciplinaryteams [70–72].

6.1. Pakistan’s Outlook. Majority of patients in Pakistan onlyreceive supportive care due to advanced stage at presentation.Yusuf and colleagues reviewed outcomes of 584 patients seenin a cancer hospital in Pakistan. Only 79 (13.5%) receiveddefinitive treatment while the rest were managed with sup-portive care [28]. TACE was the most frequent treatmentadministered in 60.7% of these 79 patients followed by PEIin 21.5% and resection in 17.7% patients. The cumulative


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probability of survival was 45%, 20%, and 10% at 1, 3, and 5years. Another study reported outcomes in 645HCCpatients.Again TACE was the most commonly used treatment in38.2% patients. All patients had BCLC stage B. Only 2.8%patients in this study had BCLC stage 0 or A HCC [9]. It isimportant to know that these results come from tertiary carehospitals which are well equipped with medical resources.Majority of patients with HCC never reach specialist facilityand we are unaware of their outcomes. Although multi-disciplinary teams have recently become more popular inPakistan, even then the majority of patients are being treatedby physicians alone and amultidisciplinary input still remainslacking [73].

7. Research on HCC

Globally, research on HCC lags behind certain other cancers,for example, breast.There is paucity of randomized trials andmost studies are retrospective clinical observations. In the last25 years, there have been 46,959 publications on breast cancerfrom the United States including 3097 clinical trials [74]. Weattempted to assess Pakistan’s contribution to HCC researchin the last 25 years. PubMed was searched for publicationsrelated to HCC from USA, UK, China, India, and Pakistan.As shown in Figure 3, China is themajor contributor forHCCresearch. A total of 6976 publications were retrieved fromChina versus 2436 from all other countries. Contribution interms of clinical trials was also higher in China as comparedto all other countries, that is, 293 versus 124, respectively.

7.1. Pakistan’s Outlook. In the last 15 years, 38 publica-tions including 2 clinical trials were conducted in Pakistan.Both these trials assessed outcomes of advanced HCC withsorafenib/gemcitabine or arterial infusion of ifosfamide [75,76]. At present, Pakistan is participating in 4 multicenterHCC clinical trials [77]. The scarcity of data on HCC

reflects upon the advanced stage at presentation when mosttreatment strategies are futile. Limitations in availability oftreatment facilities in Pakistan are a contributing factor [13].Very few centers in Pakistan offer surgical resection forHCC and liver transplantation was not offered at all untilrecently [78, 79]. Treatment facilities for PEI, RFA, and TACEare inadequate and are available predominantly to affordingpatients who only represent a minor fraction of patientssuffering from HCC in Pakistan.

8. Discussion

8.1. National Screening Program. Majority of HCC in Pak-istan is hep-C related. Even today, we remain unaware ofthe exact prevalence of hep-C in Pakistan. It is assumed thataround 10 million people in Pakistan are infected with hep-C[80, 81]. It is imperative to have a national hep-C and hep-B screening program. This would allow correct estimates ofdisease burden in our population and present true pictureof viral hepatitis. It has been shown that patients diagnosedwithHCC during surveillance have less advanced disease, aremore likely to be eligible for curative treatment, and are likelyto have increased survival [82]. Table 1 represents variousobstacles and probable solutions for HCC management inPakistan.

8.2. Public Education. Hepatitis C and hepatitis B are bothpreventable. People in Pakistan generally remain unawareof risk factors and need to be educated regarding modesof spread and necessary precautions [83, 84]. Appropriateblood product screening, prohibition of reuse of syringes,sterilization of instruments for circumcision, dental proce-dures, hair cutting, and shaving may tremendously reducethe incidence of hep-C and hep-B infection [85]. Audiovisualdissemination of risk factors for hepatitis and its impact onhealth outcomes needs to be communicated to the public. In


Table 1: Guidelines for HCC management in Pakistan.

Issues Potential solutionsIncidence and prevalence of hepatitis C and hepatitis B areunknown Implementation of national screening program

Lack of awareness regarding risk factorsLow screening rateHigh prevalence of diabetes and obesity

Public education via audiovisual dissemination regarding risk factorprevention, maintenance of healthy life style, and exercise

Insufficient HPB/liver transplant, palliative care, and cancer centersEnormous demand and supply gap

Development of infrastructure with collaboration of public andprivate sector

Shortage of technical skills Acquire technical skills via international exposure and collaboration

Controversial aspects of HCC managementKnowledge gap

Collective decision makingOnline tumor boardsPersonalized care for individual patients

Low remission rates for hepatitis C Access to new treatments at affordable price

Physician shortage Train future caregiversIncentivization

Scattered cancer registriesTrue cancer incidence and prevalence unknown National cancer registry

addition patients infected with hepatitis should understandbenefits of strict surveillance and treatments available forHCC. Figure 4 demonstrates the BCLC staging algorithm.Based on results from Pakistan, only 10% patients present inearly stage and have the potential to be cured. Unfortunately90%patients present in advanced stage and are not candidatesfor curative therapy. Our short term goal should be thedevelopment of palliative care facilities and better provisionof TACE and Sorafenib to patients with advanced HCC.Indeed palliative care is one of the most ignored specialtiesin Pakistan. In the long term, we need to develop facilitiesto detect HCC early and increase patient pool eligible forcurative therapy. Physician and public awareness regardingrisk factors for HCC, screening in the presence of risk factors,and information on treatments available (what and where) inPakistan is required.

8.3. Diabetes and Obesity. According to International Dia-betes Federation, Pakistan is among the leading countrieswith high prevalence of DM and more than 20% populationis suffering from diabetes [86, 87]. As high as 50% patientswith non-hep-B/C HCC have diabetes in Pakistan [9]. It hasbeen shown that patients withHCC and diabetes treated withSorafenib and metformin have poor outcomes comparedwith patients with HCC alone due to tumor aggressiveness inthe diabetic group [88]. Sedentary life style has contributedenormously. General public needs to be educated regardingassociation of obesity/diabetes with multiple cancers andinclusion of healthy life style and balanced diet in daily life.

8.4. Development of Infrastructure. Only a handful of centersin Pakistan provide facilities for TACE, RFA, and PEI. AsHCC incidence rises, the demand and supply gap will widensignificantly. At least one center in every major city should beplanned.This can take pressure off from the more specializedcenters and long waiting times for treatment can be avoided.

8.5. Acquire Technical Skills. Surgical resection for early stageHCC is performed only in a few centers in Pakistan. Livertransplantation was not offered until 2012, but it is offerednow in Islamabad and Lahore. Overall, surgical care for HCCpatients is compromised and there is lack of technical skillsas specialized HPB centers are emerging but are yet notestablished. Technical skills for TACE, RFA, and PEI are alsorestricted to a few centers and population at large is not beingbenefited. Public sector needs to come forward and attemptto acquire skills and facilities so that they can be provided tocommunity at large.

8.6. Communication, Collective Decision Making. HCC is adifficult disease to manage. There is an array of stagingalgorithms and wide variations exist in the use of treatmentmodalities. HCC management should be performed collec-tively by multidisciplinary teams and personalized approachto patient care should be idealized. For physicians managingHCC patients in suburban/rural regions, an online MDT canbe established to aid better decision making.

8.7. New Treatments. After years of research, we are facingan interesting period where new drugs for hepatitis C will beapproved every year. In late 2013, Sofosbuvir was approved byFDA in USA and European Medicine Agency in early 2014.In a phase III randomized trial, Sofosbuvir and Ledipasvirhave shown a sustained viral response of >96% [89]. A 12-week course of Sofosbuvir can cost up to 84000 US dollars[90]. The cost has great implications in terms of its avail-ability in low income countries. In 2006, Egypt developedhighly specialized centers for treatment of hepatitis C andbrought the cost of Peg-interferon and ribavirin down to<10% of its cost in USA via successful negotiations with thepharmaceutical companies. Within 6 years of this program,300,000 Egyptians were treated [91]. Fortunately, similarnegotiations have resulted in a reduction in cost of Sofosbuvirfor South Asian patients. It is available in 3000 dollars at


HCC

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TACE Sorafenib Best supportive care

Target: 20%OS: 20 months

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Figure 4: BCLC staging and relative distribution of Pakistani patients at the time of presentation. (Adapted from [15]).

appointed places in Pakistan. A sustained commitment fromPakistani government can ensure easy availability of thesedrugs to treat more patients. More transplant centers needto be developed as transplant provides one of the best formsof definitive treatment for patients with HCC. Internationallythere is a growing debate over expansion of donor criteria forliver transplant [92]. Better systemic chemotherapy, targetedagents, and immune therapy need to be developed due tolimited impact of existing systemic therapies [93]. Variousgenetic and molecular pathways have been explored. It hasbeen suggested that understanding of epigenetic and geneticprocesses inHCCmight help overcome therapeutic strandingin HCC [94].

8.8. Training Future Caregivers. At present, very few physi-cians return to Pakistan after receiving advanced trainingin other countries. Local doctors interested in treatment ofpatients with liver diseases should be contracted for trainingand offered viable positions to ensure adequate numbers ofhealthcare personnel in the country.

8.9. National Cancer Registry. It is high time that a nationalcancer registry is developed. We need to have correct esti-mates of healthcare burden in general and cancer in partic-ular in our population. It is difficult to develop a nationalpolicy/guideline based on results of scattered registries or

hospital data. The true incidence and prevalence of variouscancers needs to be registered so that a national action plancan be developed accordingly.

9. Conclusion

HCC in Pakistan is likely to consume significant hospitalresources and drain a sizeable chunk of health budget inthe future. Although HCC is a multifaceted disease, itlargely remains preventable. Surprisingly, general populationremains unaware of simple measures that can drasticallyreduce its occurrence. A balanced approach is requiredin trying to combat HCC. Prevention, surveillance, andappropriate treatment can significantly improve outcomesand decrease incidence of HCC in Pakistan.

Conflict of Interests

None of the authors have any conflict of interests.

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